title: LMP1 antagonizes WNT/β-catenin signalling through inhibition of WTX and promotes nasopharyngeal dysplasia but not tumourigenesis in LMP1(B95-8) transgenic mice.
abstract: Latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) can induce cell transformation and tumourigenesis, but the mechanism is not understood. Previous studies have suggested that LMP1 acts through up-regulation of cellular proliferation pathways including the Wnt/β-catenin pathway, in which β-catenin is the central effector. Increased levels of β-catenin coupled with a decrease in E-cadherin lead to reduced cell adhesion. This pathway is antagonized by WTX (Wilms' tumour gene on the X chromosome), which can promote the ubiquitination and degradation of β-catenin. In the present study, we established L2/LMP1B(95 - 8) /EGFP transgenic mice to investigate the in vivo role of LMP1. Down-regulation of WTX and E-cadherin was accompanied by increased expression of β-catenin in these mice. Even though invasive tumours did not develop, dysplasia was seen in the nasopharynx and oropharynx epithelium of these transgenic mice. Analysis of LMP1(+) , WTX(+) , and LMP1 siRNA silenced HNE-1 cell lines demonstrated that WTX could exert a dominant role in LMP1-mediated WNT/β-catenin pathway regulation. This study indicates that LMP1 antagonizes the WNT/β-catenin pathway by inhibiting WTX, and this reduction in WTX is associated with epithelial dysplasia via regulation of the WNT/β-catenin pathway molecules E-cadherin and β-catenin. Further studies are required for a better understanding of the relationship between LMP1-mediated antagonization of the WNT/β-catenin pathway and tumourigenesis.
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: QingLing
authors.forename: Yu
authors.initials: Y
authors.lastname: LiNa
authors.forename: Liu
authors.initials: L
authors.lastname: Li
authors.forename: Wang
authors.initials: W
authors.lastname: Shuang
authors.forename: Yang
authors.initials: Y
authors.lastname: YuFang
authors.forename: Ding
authors.initials: D
authors.lastname: Yi
authors.forename: Jeevan
authors.initials: J
authors.lastname: Divakaran
authors.forename: Li
authors.initials: L
authors.lastname: Xin
authors.forename: Ding
authors.initials: D
authors.lastname: YanQing
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D016162:Genes, Wilms Tumor / Q000502:physiology*; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology
chemical_list: C517118:AMER1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D014763:Viral Matrix Proteins; D051153:Wnt Proteins; D051176:beta Catenin